1. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 1 Lecture 6 – Prevention Understanding the rationale for disease prevention and early intervention (screening) Mathew J. Reeves BVSc, PhD Associate Professor, Epidemiology EPI-546 Block I

2. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 2 Objectives - Concepts 1. Primary (1 o ), Secondary (2 o ), and Tertiary (3 o ) prevention 2. Population-level vs. individual-level prevention 3. Screening (secondary prevention) Mass screening vs. case-finding 4. Screening concepts Pre-clinical phase, lead time, test Se & Sp, importance of trials, DSMR 5. Screening Biases (Observational studies) Lead-time, Length-time, and Compliance 6. Assessing the feasibility of screening 7. Risks (Harms) vs. Benefits

3. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 3 Objectives - Skills 1. Identify examples of 1 o, 2 o, and 3 o prevention 2. Communicate the pros and cons of screening 3. Explain the importance of selection bias, lead-time and length-time bias in screening programmes 4. Understand how to evaluate the efficacy of screening (trials)

4. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 4 Primary (1 o ) Prevention Defn: the protection of health by personal and community-wide efforts with a focus on the whole population Objectives: To prevent new cases of disease occurring and therefore reduce the incidence of disease Where and How?: Population-level Individual level

5. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 5 1 o Prevention @ Population-level By reducing exposure to causal (risk) factors –e.g., reducing smoking initiation in teenagers By adding a factor that prevents disease –e.g., vaccination, water fluoridation Usually requires policy and/or legislation –Smoking = tobacco taxes, restrictions on smoking indoors –Physical activity = structural changes to the environment sidewalks, walking paths, bike lanes (Town planning) Primary prevention at the population-level works best when it is driven by changes in societal attitudes –e.g., drinking and driving, bikes lanes

6. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 6 1 o Prevention @ Individual-level By removing or lowering risk factors in at-risk patients Occurs at the patient-physician level Rationale behind the periodic health exam (PHE) –e.g., smoking cessation counseling –e.g., risk factor screening in at-risk patients (BP, BC, Physical inactivity, abdominal obesity) Distinction between primary prevention and secondary prevention hinges on the presence of existing disease –Primary prevention = no existing disease

7. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 7 Secondary (2 o ) Prevention Defn: measures available for the early detection and prompt treatment of health problems Objectives: To reduce the consequences of disease (death or morbidity) by screening asymptomatic patients to identify disease in its early stages and intervening with a treatment which is more effective because it is being applied earlier. It cannot reduce disease incidence Where and how do we screen?: Population-level or mass screening Individual-level screening or case finding

8. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 8 Screening – two different approaches Population-level screening National level policy decision to offer mass screening to a whole sub-group of a population –e.g., mammography screening (women 40+) –e.g., Vision and hearing screening of all Michigan 2 nd graders Individual-level screening Occurs at the individual patient-physician level Also refereed to case finding –e.g., BP screening every time you visit MD –e.g., PSA screening Also a component of the PHE. Focus is on identifying existing disease in patients who don’t know they have it.

9. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 9 Tertiary (3 o ) Prevention Defn: measures available to reduce or eliminate long- term impairments and disabilities, minimize suffering, and promote adjustments to irremediable conditions Objectives: To reduce the consequences of disease (esp. complications and suffering) by treating disease and/or its direct complications in symptomatic patients. A proactive approach to medical care may involve rehabilitative and/or palliative care Examples –education about disease management (asthma) –regular foot exams in diabetics –pain management in hospice patients

10. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 10 Example - Fire Prevention Primary (prevent fires from starting) Education (Smokey the Bear) Outside fire bans (drought) Secondary (early detection) Smoke detectors Lookout towers Tertiary (reduce consequences) Fire brigades & smoke jumpers Fire resistant construction

11. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 11 Prevention – A Reality Check Very few preventive interventions are cost saving e.g., childhood vaccination, seatbelts Almost all preventive interventions – even those that work well - cost money!! e.g., Mam screening $40,000 per YLS Prof. Geoffrey Rose, 1992 There is only one rationale to do prevention and that is ethical

12. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 12 Prevention – A Reality Check Compared to the traditional clinical treatment (curative) approach, effective clinical prevention is hard to sustain because: Its much less effective (as measured by NNT) –NNT for 1 year statin use for stroke 1 o prevention = >13,000 –NNT for lifetime seatbelt use = 400 Prevention Paradox: A measure that provides large benefit to the community may offer little to most individuals.

13. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 13 Screening - Introduction Objective: to reduce mortality and/or morbidity by early detection and treatment. Secondary prevention. Asymptomatic individuals are classified as either unlikely or possibly having disease. Important distinction between mass or population-based screening and case finding. The allure of screening brought on by new technology is almost irresistible…..

14. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 14

15. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 15 Screening - Introduction Effective screening involves both diagnostic and treatment components Screening differs from diagnostic testing:

16. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 16 I. Important Concepts in Screening The Pre-Clinical Phase (PCP) the period between when early detection by screening is possible and when the clinical diagnosis would normally have occurred. Pathology begins Disease detectable Normal Clinical Presentation Pre-Clinical Phase

17. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 17 Pre-clinical Phase (PCP) Important to know PCP since it helps determine: Expected utility of screening –Colorectal cancer = 7-10 years –Childhood diabetes = 2-6 months Required minimal frequency of screening –Mam screening women 40-49 = 1-2 years –Mam screening women 50-69 = 3-4 years Prevalence of PCP indicates how much early disease there is to detect Prevalence of PCP is affected by: disease incidence, average duration of the PCP, previous screening, sensitivity of the test …..see concept of Prevalence pool (Lecture 3)

18. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 18 Lead Time Lead time = amount of time by which diagnosis is advanced or made earlier Pathology begins Disease detectable Normal Clinical Presentation Lead Time Screen

19. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 19 Fig 1. Relationship between screening, pre-clinical phase, clinical phase and lead time (Survival = 2yrs) (‘Survival’ = 5yrs)

20. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 20 Lead Time Equals the amount of time by which treatment is advanced or made “early” Not a theory or statistical artifact but what is expected and must occur with early detection Does not imply improved outcome!! Necessary but not sufficient condition for effective screening.

21. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 21 II. Characteristics of screening tests a) Sensitivity (Se) (Prob T+|D+) Defn: the proportion of cases with a positive screening test among all individuals with pre-clinical disease Want a highly Se test in order to identify as many cases as possible…… but there’s a trade off with……

22. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 22 II. Characteristics of screening tests b) Specificity (Sp) (Prob T-|D-) Defn: the proportion of individuals with a negative screening test result among all individuals with no pre-clinical disease The feasibility and efficiency of screening programs is acutely sensitive to the PVP which is often very low due to the very low disease prevalence e.g., PVP of +ve FOBT for CR CA = < 10% N.B. Imperfect Sp affects many (the healthy), whereas an imperfect Se affects only a few (the sick)

23. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 23 III.Evaluation of Screening Outcomes How do we know if screening is helpful? RCT Compare disease-specific mortality rate (DSMR) between those randomized to screening and those not Eliminates all forms of bias (theoretically) But, problems of: –Expense, time consuming, logistically difficult, contamination, non-compliance, ethical concerns, changing technology. Can also evaluate screening programmes using Cohort and Case-control studies, but they are difficult to do and very susceptible to bias.

24. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 24 The only valid measure of screening is… Disease-specific Mortality Rate (DSMR) the number of deaths due to disease Total person-years experience The only gold-standard outcome measure for screening NOT affected by lead time when calculated from a RCT - not affected by compliance bias or length-time bias. However, there can be problems with the correct assignment of cause of death (hence some researchers advocate using only all-cause mortality as the outcome).

25. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 25 Example of a RCT reporting DSMR to measure efficacy of FOBT screening on Colorectal CA Mortality (Mandel, NEJM 1999)

26. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 26 IV. Biases that effect screening studies Observational studies and especially survival data are acutely sensitive to: 1. Compliance bias (Selection bias): –Volunteers or compliers are better educated and more health conscious – thus they have inherently better prognosis 2. Lead-time bias –Apparent increased survival duration introduced by the lead time that results from screening. –Screen-detected cases survive longer event without benefit of early treatment (review Fig 2 in course notes). 3. Length-time bias –Screening preferentially identifies slower growing or less progressive cases that have a better prognosis.

27. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 27 Length-time bias – cases with better prognosis detected by screening SCREENING DX X X X X Better Prognosis Cases Worse Prognosis Cases

28. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 28 V. Pseudo-disease and Over-diagnosis Over-diagnosis Limited malignant potential Extreme form of length-biased sampling Examp: Pap screening and cervical carcinoma Competing risks Cases detected that would have been interrupted by an unrelated death Examp: Prostate CA and CVD death Serendipity Chance detection due to diagnostic testing for another reason Examp: PSA and prostate CA, FOBT and CR CA

29. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 29 Over-diagnosis – Effect of Mass Pap Screening in Connecticut (Laskey 1976) Age-adj. Incidence Rate (per 100,000) YearIn-situInvasiveTotal% In-situ 1950-543.818.121.917 1955-599.717.126.836 1960-6418.813.632.458 1965-6928.611.640.271 1970-7332.810.943.775

30. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 30 VI. Assessing the feasibility of screening Burden of disease Effectiveness of treatment without screening Acceptability Convenience, comfort, safety, costs (= compliance) Efficacy of screening Test characteristics (Se, Sp) Potential to reduce mortality Efficiency Low PVP Risks and costs of follow-up of test positives Cost-effectiveness –Annual Mam screening (50-70 yrs) = $30 – 50,000 /YLS –Annual Pap screening (20-75 yrs) = $1,300,000 YLS Balance of risks (harms) vs. benefits

31. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 31

32. Mathew J. Reeves, PhD © Dept. of Epidemiology, MSU 32 Feasibility Efficacy Effectiveness Cost-effectiveness Should we screen? (scientific) Can we screen? (practical) Is it worth it? (scientific, practical, policy, political) Three questions to ask before screening: